IWWM-12 2024 | An update on the BRAWM trial: fixed-duration bendamustine, rituximab, and acalabrutinib in WM

Well, the BRAWM trial is a Phase II investigator-sponsored trial that consists of a triple drug combination for newly diagnosed patients with Waldenstrom’s macroglobulinemia. The idea behind the trial was to combine treatments that have been used in different parts of the world as a single treatment. So we’ve, in many parts of the world, bendamustine and rituximab has used this first-line treatment and in some parts, BTK inhibitors are. So we said, let’s combine bendamustine and rituxab together with a next-generation BTK inhibitor, which is a acalabrutinib, to see if we could achieve deeper responses in patients undergoing their first treatment for Waldenstrom’s macroglobulinemia. So the primary endpoint is to look at CR and VGPR rates, which is a measurement of a deep response. The treatment is a fixed-duration treatment. So that’s a little different than how BTK inhibitors are used most of the time in various different B-cell lymphoproliferative disorders where they’re given continuously. We’re giving acalabrutinib for only one year. For the first six months of the acalabrutinib, it’s combined with the chemotherapy bendamustine rituxab which is given every month for six months and then the acalabrutinib is given as monotherapy for six months and then treatment is stopped and we monitor these patients. The patients have disease assessments before starting treatment which includes blood work, imaging, bone marrow assessments and in addition we do very detailed assessments sequentially for MRD and we do MRD from the peripheral blood and bone marrow, we do them every six months and that’s another way of measuring how deep the response is. This is a novel part of the trial, it’s sort of a translational part of the trial and we’re now accumulating a lot of data with the MRD assessment. So we have achieved our expected accrual which is 63 patients. The accrual, the sample size, is based upon demonstrating that the CR and VGPR is at least better than what we expect the CR and VGPR rate is for patients undergoing either bendamustine rituximab treatment alone or a BTK inhibitor therapy alone so that the lower limits of the confidence interval around our response rate will be better than what we expect that response rate to be which is we calculated to be 23 percent. So we have 50 patients who are currently evaluable for efficacy. Ten patients are still on treatment and haven’t yet reached the first efficacy time point. But already we have demonstrated that our VGPR and CR rate is 63% at the best time point or that’s our best response at any time point six months or 12 months or 18 months and that has basically achieved our primary endpoint expectation of being better or having a confidence interval that’s better than the lowest than the expected response rate for the therapies alone. The safety profile is basically what we expect. There are no unexpected toxicities. We see toxicities that are related to bendamustine or rituximab as you would expect, neutropenia, some cytopenias and we see some toxicities that are what we would expect from a BTK inhibitor. And then the exciting part is that when we look in the peripheral blood over 90% of our patients have become MRD negative in the peripheral blood at six months and it persists for 12 and 18 months so far where we have data from and in the bone marrow we don’t see quite as high a rate of MRD negativity but we have about a 25% MRD negativity in the bone marrow. So all of this is telling us that we have achieved what we hoped we would achieve which is getting very deep responses in patients who are undergoing their first treatment for Waldenstrom’s. We expect that these results will translate into long durations of response long progression free survival and hopefully long survival but of course we have to follow these patients further.